National Institute of Allergy and Infectious Diseases | health information GATA2 Deficiency NIAID GATA2 deficiency is a rare disorder of the immune system with wide-ranging effects. First identified in 2011, the disorder is char- acterized by immunodeficiency, myelodys- plastic syndrome (a condition characterized by ineffective blood cell production), lung dis- ease, and problems of the vascular/lymphatic system. GATA2 deficiency is diagnosed based on clinical findings, laboratory tests, and Genetics primer: All the cells in the body contain instructions on how to do their job. These instructions are packaged into genetic testing. Early diagnosis is critical for chromosomes, each of which contains many genes. Genes are optimal disease management, prevention of units of inheritance that are made up of DNA and encode proteins. An error, or mutation, in a gene can cause disorders such as severe complications, treatment, and evalua- GATA2 deficiency. Credit: NIAID tion of at-risk relatives. Genetics and Function GATA2 deficiency is caused by germline mutations in the GATA2 gene. Germline means that the mutation is present in every cell in the body, not just the immune system cells. The GATA2 gene produces a protein called a transcription factor. Transcription factors regulate when other genes are turned on. The GATA2 transcription factor helps regu- late blood cell differentiation, the process by which blood stem cells give rise to special- ized types of blood cells. When this process does not work properly, people are at risk of developing a wide range of symptoms. Stem cells in the bone marrow produce the many types of blood Everyone has two copies of the GATA2 and immune system cells through a process called differentiation. GATA2 helps regulate the early steps in this process. Credit: © 2007 gene—one inherited from the mother and Terese Winslow. U.S. Govt. has certain rights. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Allergy and Infectious Diseases one from the father. The mechanism underlying GATA2 deficiency is called “haploinsufficiency.” This means that having one mutated copy of GATA2 and one working copy of GATA2 is insufficient for normal functioning of the hematopoietic, or blood- making, system. Many different germline GATA2 mutations have been reported. These can broadly be categorized as missense, null, and regulator mutations (see Glossary). Approximately 5 percent of people with the clinical symptoms A schematic of the GATA2 gene and protein. In panel A, the five protein-coding parts (exons) of the gene are shown as dark boxes, and the non-protein-coding of GATA2 deficiency have no detect- parts are the interspersed lines. The exons are stitched together and translated able GATA2 mutations, suggesting into the protein shown in panel B. Panel C contains an enlargement of the protein’s ZF-2 region. Null mutations are shown in red, regulator mutations are an important role for undiscovered shown in blue, and missense mutations are shown in green. Credit: NIAID regulatory regions. Inheritance GATA2 deficiency is inherited in an autosomal dominant manner, which means that a person needs only one abnormal GATA2 gene copy to have GATA2 deficiency. Dominant inheritance usually means that relatives from the side of the family with the mutation also have symp- toms of GATA2 deficiency. These symptoms are typically not present at birth but develop over time. By age 20, about 50 percent of people with a GATA2 mutation have symptoms. By age 60, however, only about 5 percent of people remain symptom-free. This phenomenon is called “incomplete penetrance.” In a family with a parent who has a GATA2 mutation, each child has a 50 percent, or 1 in 2, chance of inheriting the mutated GATA2 gene. Importantly, the chance of one child inheriting the mutation is independent of whether In this example, a man with an autosomal his or her siblings have the mutation. In other words, dominant disorder has two affected children and if the first three children in a family have the mutation, two unaffected children. Women also can pass on the mutation. Credit: U.S. National Library of the fourth child still has a 50 percent chance of inheriting Medicine it. Children who do not inherit the abnormal gene will not develop GATA2 deficiency or pass on the mutation. Often, the initial diagnosis in a family will initiate a cascade of genetic testing in relatives who are at risk for having inherited the mutation. NIAID 2 Some GATA2 mutations are not inherited but rather arise spontaneously, or de novo, in the patient. De novo mutations are the result of a mutation in the parent’s sperm or egg or in the fertilized egg itself. Everyone is born with de novo mutations throughout their genomes, but people usually only find out about mutations that occur in important genes such as GATA2. Clinical Features The clinical features of GATA2 deficiency are wide-ranging both in type and severity. For exam- ple, one person may have severe viral infections causing recalcitrant warts; another may develop acute myeloid leukemia; and another’s only symp- tom may be hearing loss. This variation in how GATA2 deficiency manifests in each person, called “variable expressivity,” can be striking, even in the same family. Generally, the disease has a progres- sive course. The main clinical features of GATA2 deficiency include the following: • Hematologic: Cytopenias, or reductions in the number of blood cells (cyto meaning cell, penia meaning too few), are common and can affect several cell types, including B cells, natural killer cells, monocytes, and T cells. The results of this can be profound. Sometimes the prob- lems with these cells progress to the point that they are formally called “myelodysplastic syndrome.” In a subset of patients, this can evolve into cancers of the blood, such as acute myeloid leukemia (AML) or chronic myelo- monocytic leukemia (CMML). Progressively worsening cytopenias are associated with other major complications of GATA2 deficiency, Clinical features of GATA2 deficiency by organ system. Common including lung problems and infections. clinical problems are indicated in bold. Credit: NIAID • Infectious: The majority of patients with GATA2 deficiency eventually develop major viral, bacterial, or fungal infections. Viral infections are the most common and may include human papillomavirus (HPV), which causes warts; severe herpesvirus; persistent Epstein-Barr virus (EBV) viremia; or molluscum contagiosum (see Glossary for more details about these infections). • Pulmonary: The main pulmonary feature of GATA2 is the development of pulmonary alveolar proteinosis (PAP). This is a rare lung disease in which a type of protein builds up in the air sacs (alveoli) of the lungs, making breathing difficult. A subset of patients with PAP go on to develop a serious type of high blood pressure that affects the arteries in the lungs and heart, called pulmonary arterial hypertension. NIAID NIAID 3 • Dermatologic: The main dermatologic symptoms are caused by the underlying immunodeficiency or hematologic problems. Persistent warts are the most common skin issue in people with GATA2 deficiency, and typically these warts are not helped by cauterization, cryotherapy, topical treatments, or laser treatments (see Glossary for more details). Chronic skin infections increase the risk of skin cancers, including squamous cell carcinoma. Skin problems due to bacteria, fungus, or lymph problems also have been reported in people with GATA2 deficiency. • Neoplastic: In addition to blood cancers, solid tumors—most commonly skin cancers—also may occur in people with GATA2 deficiency. A number of other types of tumors have been seen, although their occurrence is rare and their association with the underlying GATA2 deficiency is unclear. • Vascular/lymphatic: A minority of patients with GATA2 deficiency may experience chronic lymphedema, swelling in an arm or leg caused by a lymphatic system blockage. • Other: Hearing loss, increased risk of miscarriage, and hypothyroidism also may be part of the clinical spectrum of GATA2 deficiency. Because GATA2 deficiency is a rare disorder, current knowledge is based on the careful study of several dozen families affected by GATA2 deficiency. As research continues, understanding of the clinical spectrum, disease course, and underlying biology will be refined. Laboratory Findings Laboratory findings can vary widely in this disease, although they typically include low levels of certain blood cells, especially B cells, natural killer cells, monocytes, and dendritic cells. Management and Treatment Treatment for GATA2 deficiency is based on a person’s clinical condition and may include medications and other strategies for managing specific infections, cytopenias, and pulmo- nary or vascular issues. Doctors may recommend the prophylactic, or preventive, use of antimicrobial drugs to prevent infections. A bone marrow transplant, also Illustration depicting a bone marrow, or hematopoietic stem cell, transplant. called a hematopoietic stem cell Credit: © 2011 Terese Winslow LLC. U.S. Govt. has certain rights. transplant, is the best long-term treatment option for many serious genetic immunodeficiency diseases. This therapy has been used to manage patients with GATA2 deficiency, and it can resolve most of their clinical symptoms and laboratory abnormalities. In this procedure, stem cells are removed from a donor, the patient receives treatment to destroy his or her own blood-forming cells, and